U.S. patent application number 09/510527 was filed with the patent office on 2002-01-31 for pharmaceutical composition for treating dysmenorrhea and premature labor.
Invention is credited to Bologna, William J, De Ziegler, Dominique, Levine, Howard L.
Application Number | 20020012677 09/510527 |
Document ID | / |
Family ID | 26738031 |
Filed Date | 2002-01-31 |
United States Patent
Application |
20020012677 |
Kind Code |
A1 |
Levine, Howard L ; et
al. |
January 31, 2002 |
Pharmaceutical composition for treating dysmenorrhea and premature
labor
Abstract
The present invention teaches a composition comprising a
.beta.-adrenergic agonist in a bioadhesive carrier. Preferably, the
composition comprises terbutaline in polycarbophil. The present
invention additionally teaches the local administration of a
.beta.-adrenergic agonist for the purpose of treating or preventing
dysmenorrhea or premature labor. Using this composition and the
method of treatment provides sufficient local levels of the drug to
provide therapeutic efficacy, but avoids many untoward adverse
events.
Inventors: |
Levine, Howard L;
(Oceanside, NY) ; Bologna, William J; (Paris,
FR) ; De Ziegler, Dominique; (Paris, FR) |
Correspondence
Address: |
SCOTT H. BLACKMAN
LYON & LYON LLP
1701 PENNSYLVANIA AVENUE
N.W. SUIT 1040
WASHINGTON
DC
20006
US
|
Family ID: |
26738031 |
Appl. No.: |
09/510527 |
Filed: |
February 22, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09510527 |
Feb 22, 2000 |
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09145172 |
Sep 1, 1998 |
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6126959 |
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60058789 |
Sep 12, 1997 |
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Current U.S.
Class: |
424/400 |
Current CPC
Class: |
A61K 31/137 20130101;
A61K 9/0034 20130101; A61K 9/006 20130101; A61P 15/00 20180101;
A61P 15/06 20180101; A61K 47/32 20130101 |
Class at
Publication: |
424/400 |
International
Class: |
A61F 013/00 |
Claims
We claim:
1. A pharmaceutical composition comprising a therapeutically
effective amount of a .beta.-adrenergic agonist together with a
pharmaceutically acceptable bioadhesive carrier.
2. The composition of claim 1 wherein the .beta.-adrenergic agonist
is terbutaline.
3. The composition of claim 2 wherein the bioadhesive carrier
comprises a cross-linked carboxylic polymer.
4. The composition of claim 3, wherein the concentration of
terbutaline is from 0.1 to 0.4% weight/weight.
5. The composition of claim 4, wherein the polymer is
polycarbophil.
6. The composition of claim 5, wherein the .beta.-adrenergic
agonist is terbutaline and the composition is prepared so that a
dosage of about 1 to 1.5 g of composition will deliver from 1 to 4
mg of terbutaline.
7. A method of preventing or treating dysmenorrhea comprising
administering vaginally to a host in need thereof the
pharmaceutical composition of claim 1.
8. The method of claim 7, wherein the .beta.-adrenergic agonist is
terbutaline and the dosage of composition administered contains
from 1 to 4 mg of terbutaline.
9. The method of claim 7, wherein the composition is administered
every 12 to 48 hours during dysmenorrhea.
10. The method of claim 7, wherein the composition is administered
every 12 to 48 hours beginning one day prior to the anticipated
onset of dysmenorrhea and continuing during dysmenorrhea.
11. The method of claim 7, wherein the composition is administered
every 24 hours during dysmenorrhea.
12. The method of claim 7, wherein the composition is administered
every 24 hours beginning one day prior to the anticipated onset of
dysmenorrhea and continuing during dysmenorrhea.
13. A method of preventing or treating premature labor comprising
administering the composition of claim 1 vaginally, in a
therapeutically effective amount.
14. The method of claim 13, wherein the .beta.-adrenergic agonist
is terbutaline and the dosage of composition administered contains
from 1 to 4 mg of terbutaline.
15. The method of claim 13, wherein the composition is administered
every 12 to 48 hours to prevent or treat premature labor.
16. The method of claim 13, wherein the composition is administered
every 24 hours to prevent or treat premature labor.
17. A pharmaceutical composition for vaginal administration of a
treating agent to achieve local efficacy without detrimental blood
levels of the treating agent, comprising a therapeutically
effective amount of a treating agent together with
polycarbophil.
18. A method of vaginally administering the composition of claim
17, in a therapeutically effective amount.
19. A pharmaceutical composition for vaginal administration of a
treating agent during menses, comprising polycarbophil and a
therapeutically effective amount of a treating agent.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/058,789, filed Sep. 12, 1997, which is
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention relates to a pharmaceutical composition and
the local administration thereof for the purpose of treating or
preventing dysmenorrhea or premature labor.
BACKGROUND OF THE INVENTION
[0003] Both dysmenorrhea and premature labor affect significant
numbers of American women; however, treatment regimens are still
lacking for both conditions. Dysmenorrhea, menstrual cramps,
affects on average over 50% of women and results in frequent
absenteeism or loss of activity. Andersch, B., Milsom I., An
Epidemiologic study of young women with dysmenorrhea, A.J.O.G.,
144:655-60 (1982). Young women report a somewhat higher incidence
of dysmenorrhea than the average, with estimates ranging from 67%
to 72%. Harlow, S. D., Parck M., A longitudinal study of risk
factors for the occurrence, duration and severity of menstrual
cramps in a cohort of college women, Br. J. Obstet. Gynaecol.,
103:1134-42 (1996). Severe pain has been reported by 7 to 15% of
women. Id.
[0004] In the United States alone an estimated 140 million work and
school hours are lost per year due to this condition. Klein, J. R.,
Litt, I. F., Epidemiology of adolescent dysmenorrhea, Pediatrics,
68:6661-64 (1981). About 42% of United States university students
between the ages of 17 and 19 have had to be absent from their
daily activities at least once due to dysmenorrhea. Id.
Approximately 15% of young women have one to three days of
incapacitation each month and dysmenorrhea is the leading cause of
short-term school absenteeism among adolescent young women. Id.
This disease, with its constant regularity, results in notable
social, educational, and economic losses in this country.
[0005] Dysmenorrhea consists of painful uterine cramping and is
often accompanied by associated symptoms including nausea,
vomiting, diarrhea, and lower backaches. Treatments for
dysmenorrhea currently focus on the use of non-steroidal
antiinflammatory drugs (NSAIDs). These drugs include, for instance,
naproxen, ibuprofen, mefenamic acid, and meclofenamate sodium. Oral
contraceptives are also used by some women in the treatment of
dysmenorrhea. Despite the fact that these two regimens can be used
together, the recurring problems of dysmenorrhea have not been
eliminated for many women.
[0006] Specifically, the painful uterine cramping associated with
dysmenorrhea is probably triggered by vasopressin and increased
production of prostaglandins. The current method of treatment, with
NSAIDs, blocks prostaglandin production and acts as a painkiller.
Although this method of treatment is effective in some women and
decreases symptoms in other women, researchers have wondered
whether blocking the dysmenorrheic process at an earlier step would
provide more effective treatment in the prevention of uterine
cramping.
[0007] Although no link has formally been established, some
researchers believe that untreated dysmenorrhea may play a role in
the genesis of such serious clinical conditions as endometriosis.
Recent studies have shown that endometriosis is associated with
dyskinetic patterns of uterine contractions at the time of menses.
Salamanca, A., Beltran, E., Subendometrial Contractility in
Menstrual Phase Visualized by Transvaginal Sonography in Patients
with Endometriosis. Fertil. Steril., 65:193-95 (1995).
Additionally, the symptoms of dysmenorrhea can often mask the more
serious disease of endometriosis. Symptoms of dysmenorrhea often
occur in women with endometriosis for nearly ten years on average
prior to laproscopic diagnosis of the later disease. Hadfield, R.,
Mardon, H., Barlow, D., Kennedy, S., Delay in the Diagnosis of
Endometriosis: A Survey of Women from the U.S.A. and U.K. Human
Reprod., 11:878-80 (1996).
[0008] Premature labor also affects a significant number of women
in the United States.
[0009] Preterm delivery is defined as delivery prior to 30 weeks of
gestation. This phenomenon complicates 8 to 10% of births in the
United States and is a leading cause of neonatal morbidity and
mortality. Lockwood, C. J., The diagnosis of PTL and the prediction
of preterm delivery, Clinical Obstetrics and Gynecology, Pitkin, R.
M., Scott, J. R. (eds.), 38:675-678 (1995). In fact, prematurity
causes 75% of perinatal deaths in this country. McCombs, J., Update
on Tocolytic Therapy, Annals of Pharmacotherapy, 29:515-522 (1995).
Premature infants also have an increased risk of other serious
conditions, including respiratory distress syndrome, hyaline
membrane disease, intracranial intraventricular hemorrhage,
necrotizing enterocolitis, sepsis, and have an increased incidence
of cerebral palsy. Id.
[0010] Currently, preventing preterm delivery focuses on the early
diagnosis of impending premature labor in women with intact
membranes. Oral tocolytic agents, or uterine relaxants, are the
treatment of choice. Tocolytic agents include progestational
compounds, .beta.-adrenergic agonists, NSAIDs, calcium agonists,
oxytocin, or vasopressin agonists, and potassium channel openers.
The most widely used of these are the .beta.-adrenergic agonists
such as terbutaline and ritodrine. It should be noted, however,
that of the .beta.-adrenergic agonists, only ritodrine is approved
by the F.D.A. for use in preterm labor. Other .beta.-adrenergic
agonists, such as terbutaline, are approved for other conditions
(e.g., asthma) but have been used by practitioners in the treatment
of premature labor. As these drugs are given orally, however,
treatment is accompanied by serious side effects. Research has
failed to produce a .beta.-adrenergic agonist that is selective for
the receptors in the uterus and consequently lacking of some of the
most serious adverse events.
[0011] Terbutaline is a .beta.-adrenergic agonist. Its chemical
formula is
5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-1,3-benzenediol.
The empirical formula of terbutaline is C.sub.12H.sub.19NO.sub.3.
Its molecular weight is 225.29. Its structural formula is as
follows: 1
[0012] Terbutaline, as a .beta.-adrenergic agonist, has been used
primarily as a bronchodilator. .beta.-adrenergic agonists exert
their pharmacologic effects by activation of adenyl cyclase, the
enzyme that catalyzes the conversion of adenosine triphosphate
(ATP) to cyclic adenosine monophosphate (cAMP). Activation of
adenyl cyclase by .beta.-adrenergic agonists increases
intracellular levels of cAMP. Cyclic AMP in turn reduces the
availability of intracellular free Ca.sup.2+, which is required for
the activation of myosin light-chain kinase, the enzyme that
phosphorylates myosin and thereby allows it to combine with actin
to form actomyosin. Lack of Ca.sup.2+ results in disruption of the
actin-myosin interaction, with resultant inhibition of smooth
muscle contractility. Due to their direct effects on smooth muscle
contractility, .beta.-adrenergic agonists, such as terbutaline, may
prove to be an effective therapy for both dysmenorrhea and
premature labor.
[0013] In fact, oral and intravenous terbutaline has been used as a
reasonably effective therapy for preterm labor. Studies have shown
that oral or IV therapy can stop contractions or postpone delivery.
Lyrenas, S., Grahnen, A., Lindberg, B., et. al., Pharmacokinetics
of Terbutaline During Pregnancy, Eur. J. Clin. Pharmacol.,
29:619-623 (1986); Berg., G., Lindberg, C., Ryden G., Terbutaline
in the Treatment of Preterm Labour, Eur. J. Respir. Dis.,
65:219-230 (1984). Adverse events can present significant problems
in the treatment of preterm labor with terbutaline and are
discussed further below.
[0014] A few studies also document the use of terbutaline in the
treatment of dysmenorrhea. In one study, treatment with IV
terbutaline inhibited myometrial activity, increased blood flow to
the uterus, and relieved the pain occurring during uterine
contractions accompanying dysmenorrhea. .ANG.kerlund, M.,
Andersson, K. E., and Ingemarsson, E., Effects of Terbutaline on
Myometrial Activity, Uterine Blood Flow, and Lower Abdominal Pain
in Women with Primary Dysmenorrhoea, Br. J. of Obstet. & Gyn.,
83(9):673-78 (1976). Terbutaline inhalers have even been evaluated
for the treatment of dysmenorrhea. Kullander, S., Svanberg, L.,
Terbutaline Inhalation for Alleviation of Severe Pain in Essential
Dysmenorrhea, Acta Obstet. Gynecol. Scand., 60:425-27 (1981). This
therapy did provide some efficacy; however, treatment was not
sufficient for most patients, who had to supplement with other
medications for adequate relief. Further, the effect of each spray
lasted as little as 1 hour. Id. One other .beta.-adrenergic
agonist, salambutol, showed pain relief when administered
intravenously. Lalos, O., Joelsson, I., Effect of Salbutamol on the
Non-Pregnant Human Uterus In Vivo, Acta Obstet. Gynecol. Scand.,
60:349-52 (1981).
[0015] Several problems with administration and adverse effects,
however, prevent women affected by dysmenorrhea and premature labor
from being able to take full advantage of this therapy. First,
.beta.-adrenergic agonists such as terbutaline have a low
bioavailability after oral administration. These pharmaceuticals
are well absorbed but have extensive first-pass sulphation.
Bioavailability has been estimated at between 15 and 20%.
Concomitant food intake additionally decreases bioavailability by a
further 30%. Bricanyl: Scientific brochure, Astra France
Laboratories (1993).
[0016] Second, adverse effects significantly limit the current
utility of terbutaline in the treatment of preterm labor and
dysmenorrhea. Placental transfer of .beta.-adrenergic agonists such
as terbutaline is relatively rapid; thus, adverse effects are
observed in the fetus and neonate while treating premature labor
using oral administration. Morgan, D. J., Clinical Pharmacokinetics
of .beta.-Agonists, Clin. Pharmacokin., 18:270-294 (1990). Thus,
when treating preterm labor, adverse events can affect not only the
woman but also her child.
[0017] The most serious adverse events are cardiovascular in
nature. Intravenous administration of terbutaline has been
associated with palpitations and peripheral tremors. .ANG.kerlund,
M., Andersson, K. F., Ingemarsson, I., Effects of Terbutaline on
Myometrial Activity, Uterine Blood Flow and Lower Abdominal Pain in
Women With Primary Dysmenorrhea. Br. J. Obstet. Gyncol., 83:673-78
(1976). As a sympathomimetic amine, terbutaline can cause problems
in patients with cardiovascular disorders (including arrhythmia,
coronary insufficiency and hypertension), as well as with patients
with hyperthyroidism, diabetes mellitus, or a history of seizures.
Significant adverse reactions have been reported following
administration of terbutaline to women in labor including pulmonary
edema and hypoglycemia in the mother and or neonate child.
Intravenous terbutaline has also been reported to aggravate
preexisting diabetes and ketoacidosis. Other adverse events
include: tremors, nervousness, increased heart rate, palpitations,
and dizziness. Less frequent adverse effects include headaches,
drowsiness, vomiting, nausea, sweating, muscle cramps, and ECG
changes.
[0018] These adverse effects have precluded the use of
.beta.-agonists such as terbutaline to prevent or treat
dysmenorrhea as it considered to be a benign or non-threatening
condition. .ANG.kerlund, M., Andersson, K. E., and Ingemarsson, E.,
Effects of Terbutaline on Myometrial Activity, Uterine Blood Flow,
and Lower Abdominal Pain in Women with Primary Dysmenorrhoea, Br.
J. of Obstet. & Gyn., 83(9):673-78 (1976). Further, the risks
involved have limited the use of these pharmaceutical agents in the
treatment of preterm delivery and premature labor as the benefits
must be balanced carefully against the seriousness of the adverse
events involved.
[0019] In an attempt to address the severity of the adverse events
involved, researchers have been attempting to identify another
effective means for administering the drug that would decrease the
risk involved. It is known that terbutaline can be administered
directly to the uterus, resulting in preferential local
concentrations as compared to peripheral circulation
concentrations. Kullander et al. studied the correlation between
the uterine and blood concentrations of terbutaline after insertion
of a terbutaline-impregnated polymer ring (10% terbutaline sulfate
in a 5 g vaginal ring), terbutaline in a cellulose gel (0.1 mg in 1
mL cellulose gel), or a placebo ring in a patient 24 hours before
hysterectomy. Kullander, S., Svanberg, L., On resorption and the
effect of vaginally administered terbutaline in women with
premature labor. Acta. Obstet. Gynecol. Scand., 64:613-16 (1985).
The methods followed in this reference, however, have distinct
disadvantages. The water soluble cellulose-gel used can wash away
and the use of a polymer ring can be uncomfortable and unpalatable
for the woman, and thus both are distinctly disadvantageous.
[0020] Other pharmaceutical compounds with problematic adverse
events have been successfully administered locally. The bioadhesive
carrier of the present invention has been used in other drug
delivery systems, although with different results than in the
present invention. For example, polycarbophil is a main ingredient
in the vaginal moisturizer Replens.RTM.. It has also been used as a
base for compositions with other active substances such as
progesterone (Crinone.RTM.) (see U.S. Pat. No. 5,543,150) and
Nonoxynol-9 (Advantage-S) (see U.S. Pat. No. 5,667,492).
[0021] Additionally, it is important that pharmaceutical
compositions do not interfere with all contractions and the
homeostasis of menstruation. As menstrual blood does not clot,
normal, regularized contractions are helpful to stop the bleeding.
If there are no contractions, then the patient may not stop
bleeding and may hemorrhage. Thus, it is an object of the invention
to interfere with the dyskinetic contractions causing dysmenorrhea,
without stopping contractions entirely.
SUMMARY OF THE INVENTION
[0022] The present invention relates to a pharmaceutical
composition comprising a therapeutically effective amount of a
.beta.-adrenergic agonist together with a pharmaceutically
acceptable bioadhesive carrier and the local administration of
.beta.-adrenergic agonist for the purpose of treating or preventing
dysmenorrhea or premature labor. Using this composition and the
method of treatment provides sufficient local levels of the drug to
provide therapeutic efficacy, but avoids many untoward adverse
events.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 illustrates the serum terbutaline levels in a single
dose study. Doses were 4 mg, 2 mg, and 1 mg. The terbutaline gel
was administered transvaginally once.
[0024] FIG. 2 illustrates the serum terbutaline levels in a
multiple dose study. Doses were 4 mg, 2 mg, and 1 mg. The
terbutaline gel was administered transvaginally once daily for six
days.
[0025] FIG. 3 illustrates the serum terbutaline levels in a single
dose study. The dose given was 8 mg. The terbutaline gel was
administered transvaginally once.
[0026] FIG. 4 illustrates the serum terbutaline levels in a
multiple dose study. The dose given was 8 mg. The terbutaline gel
was administered transvaginally once daily for six days.
[0027] FIG. 5 illustrates mean heart rates in a single dose study.
Doses were 8 mg, 4 mg, 2 mg, and 1 mg. The terbutaline gel was
administered transvaginally once.
[0028] FIG. 6 illustrates mean heart rates in a multiple dose
study. Doses were 8 mg, 4 mg, 2 mg, and 1 mg. The terbutaline gel
was administered transvaginally once daily for six days.
[0029] FIG. 7 illustrates the myometrial terbutaline influx in an
ex vivo uterine perfusion model.
DETAILED DESCRIPTION OF THE INVENTION
[0030] The present invention is related to a composition comprising
therapeutically effective amount of a .beta.-adrenergic agonist
together with a pharmaceutically acceptable bioadhesive carrier.
Preferably terbutaline is used as the .beta.-adrenergic agonist.
The present invention preferably comprises a .beta..sub.2 specific
adrenergic agonist. Other acceptable .beta.-adrenergic agonists
include ritodrine, isoxsuprine, fenoterol, salambutol,
hexoprenaline, metaproterenol, bitolterol and pirbuterol. The
invention comprises a uterine smooth muscle relaxant for both
pregnant and non-pregnant women and has been specifically designed
for vaginal administration. The bioadhesive carrier, which may be
in a gel formulation, contains a polycarbophil base designed to
give controlled and prolonged release of terbutaline, or another
.beta.-adrenergic agonist, through the vaginal mucosa. This route
of administration avoids first-pass metabolism problems. The direct
delivery to the uterus allows for lower systemic drug
concentrations. These two properties help avoid many significant
adverse events.
[0031] The present invention is additionally related to a method of
preventing or treating dysmenorrhea comprising administering the
composition vaginally. Additionally, the present invention includes
a method of preventing or treating premature labor comprising
administering the composition vaginally. Most preferably, in
preventing or treating both conditions, 1 to 1.5 g of the
composition is administered; although, acceptable amounts of the
composition to be administered include 0.5 to 2.5 g. The
composition administered can contain between 1 to less than about 8
mg of terbutaline per dose, preferably containing 1 to 4 mg, and
most preferably containing 2 to 4 mg. Dosages of 8 or more mg are
not recommended, however, because side effects may be noted in some
individuals at such levels. The composition can be administered
every 12 to 48 hours, but is preferably administered every 24
hours. The composition can be administered during dysmenorrhea or
optionally including one or more days prior to the anticipated
onset of dysmenorrhea. Similarly, the composition may be
administered during premature labor or to prevent the onset of
anticipated premature labor.
[0032] The present invention comprises a dosing regimen and manner
of treating dysmenorrhea. In practicing the invention, a patient
need not wait until the onset of menses and the occurrence of pain
to begin treatment. The present invention comprises administration
of the composition as soon as the patient realizes that she is
nearing the onset of menses, for example within a day or two. This
method of administration is based on pharmacokinetic data below,
and prevents the process of dyskinetic contractions from occurring,
rather than treating them once the contractions have already
begun.
[0033] Another important aspect of the invention is that the
uterorelaxant formulation can correct dysmenorrhea and its
dyskinetic contractions, without interfering with the normal
contractions and bleeding during menstruation. Dysmenorrhea appears
to involve dyskinetic contractions, which are erratic and abnormal.
This is in contrast to other theories of dysmenorrhea as comprises
solely an increase in the amplitude and frequency of contraction.
The inventors believe that in dysmenorrhea the nature of
contractions change so that there are not only antegrade
contractions (fundus to cervix), but also retrograde contractions
(cervix to fundus), and non-functional fibrillations. The
composition of the present invention appears to provide relief by
way of a selective action on the dyskinetic contractions without
preventing the normal, regularized contractions necessary for
menstruation.
[0034] The specific drug delivery formulation chosen and used in
the examples below comprises a cross-linked polycarboxylic acid
polymer formulation, generally described in U.S. Pat. No. 4,615,697
to Robinson (hereinafter "the '697 patent"), which is incorporated
herein by reference. In general, at least about eighty percent of
the monomers of the polymer in such a formulation should contain at
least one carboxyl functionality. The cross-linking agent should be
present at such an amount as to provide enough bioadhesion to allow
the system to remain attached to the target epithelial surfaces for
a sufficient time to allow the desired dosing to take place.
[0035] For vaginal administration, such as in the examples below,
preferably the formulation remains attached to the epithelial
surfaces for a period of at least about twenty-four to forty-eight
hours. Such results may be measured clinically over various periods
of time, by testing samples from the vagina for pH reduction due to
the continued presence of the polymer. This preferred level of
bioadhesion is usually attained when the cross-linking agent is
present at about 0.1 to 6.0 weight percent of the polymer, with
about 1.0 to 2.0 weight percent being most preferred, as long as
the appropriate level of bioadhesion results. Bioadhesion can also
be measured by commercially available surface tensiometers utilized
to measure adhesive strength.
[0036] The polymer formulation can be adjusted to control the
release rate of the .beta.-adrenergic agonist, such as terbutaline,
by varying the amount of cross-linking agent in the polymer.
Suitable cross-linking agents include divinyl glycol,
divinylbenzene, N,N-diallylacrylamide, 3,4-dihydroxy-1,5-hexadiene,
2,5-dimethyl-1,5-hexadiene and similar agents.
[0037] A preferred polymer for use in such a formulation is
Polycarbophil, U.S.P., which is commercially available from B. F.
Goodrich Speciality Polymers of Cleveland, Ohio under the trade
name NOVEON.RTM.-AA1. The United States Pharmacopeia, 1995 edition,
United States Pharmacopeial Convention, Inc., Rockville, Md., at
pages 1240-41, indicates that polycarbophil is a polyacrylic acid,
cross-linked with divinyl glycol.
[0038] Other useful bioadhesive polymers that may be used in such a
drug delivery system formulation are mentioned in the '697 patent.
For example, these include polyacrylic acid polymers cross-linked
with, for example, 3,4-dihydroxy-1,5-hexadiene, and polymethacrylic
acid polymers cross-linked with, for example, divinyl benzene.
[0039] Typically, these polymers would not be used in their salt
form, because this would decrease their bioadhesive capability.
Such bioadhesive polymers may be prepared by conventional free
radical polymerization techniques utilizing initiators such as
benzoyl peroxide, azobisisobutyronitrile, and the like. Exemplary
preparations of useful bioadhesives are provided in the '697
patent.
[0040] The bioadhesive formulation may be in the form of a gel,
cream, tablet, pill, capsule, suppository, film, or any other
pharmaceutically acceptable form that adheres to the mucosa and
does not wash away easily. Different formulations are further
described in the '697 Patent, which is incorporated herein by
reference.
[0041] Additionally, the additives taught in the '697 patent may be
mixed in with the cross-linked polymer in the formulation for
maximum or desired efficacy of the delivery system or for the
comfort of the patient. Such additives include, for example,
lubricants, plasticizing agents, preservatives, gel formers, tablet
formers, pill formers, suppository formers, film formers, cream
formers, disintegrating agents, coatings, binders, vehicles,
coloring agents, taste and/or odor controlling agents, humectants,
viscosity controlling agents, pH-adjusting agents, and similar
agents.
[0042] The specific preparation (COL-2301) used in the studies
discussed in the examples consists of the following
ingredients.
1TABLE 1 Preferred Compositions Active Ingredient mg/g 1.0 2.0 4.0
Terbutaline (sulfate) % (w/w) 0.1% 0.2% 0.4% Purified Water 755.4
754.4 752.4 Glycerin 139.0 139.0 139.0 Light liquid paraffin 42.0
42.0 42.0 Carbomer 934P 30.0 30.0 30.0 Polycarbophil 20.0 20.0 20.0
Methylparaben 1.8 1.8 1.8 Sorbic acid 0.8 0.8 0.8 Sodium Hydroxide
0.0-2.0 0.0-2.0 0.0-2.0 LABRAFIL .RTM. M2130 10 10 10
[0043] Carbomer is a gel former, preferably Carbopol 934P, but may
be substituted by other gel formers including, but not limited to,
Carbomer 974P, Carbomer 980, methyl cellulose or propyl
cellulose.
[0044] LABRAFIL.RTM. M2130 is a lubricant/whitening agent to
provide lubricity and add color to the gel; alternatives may be
used, and coloring may be left out altogether.
[0045] Glycerin is a humectant; alternative humectants include, for
example, propylene glycol or dipropylene glycol.
[0046] Preparation of the formulation involves hydration of the
polymers, separate mixing of water-soluble ingredients (the
"polymer phase") and oil-soluble ingredients (the "oil phase"),
heating and mixing of the two phases, and homogenization of the
mixture. All ingredients in COL-2301 are well known and readily
available from suppliers known in the industry.
[0047] The polymer phase may generally be prepared by mixing the
water (with about 3% excess volume of water to account for
evaporative losses), sorbic acid, and methylparaben together. This
mixture is heated to 75.degree. C. The solution is cooled,
generally to room temperature, and then the polycarbophil and
Carbomer are added. The polymers are hydrated by mixing for several
hours, generally about 2-3 hours until a uniform, smooth,
homogenous, lump-free gel-like polymer mixture is obtained. When
the polymers are completely hydrated, the terbutaline is added and
mixed in, until a homogeneous suspension is obtained.
[0048] The oil phase is generally prepared by melting together the
LABRAFIL.RTM. M2130, glycerin, and light liquid paraffin, by
heating to 75 to 78.degree. C. The mixture is cooled to about
60.degree. C., while the polymer phase is warmed to about the same
temperature. The polymer phase is then added to the heated oil
phase. The two phases are mixed thoroughly, producing a uniform,
creamy white product. Sodium hydroxide is added, as needed, to
produce a pH of about 2.5-4.5, generally about 4. When the mixture
has cooled, it is de-aerated.
[0049] As will be apparent to those skilled in the art, the
composition of the formulation can be varied to affect certain
properties of the formulation. For example, the concentration of
the bioadhesive polymer can be adjusted to provide greater or
lesser bioadhesion. The viscosity can be varied by varying the pH
or by changing the concentration of the polymer or gel former. The
relative concentrations of the oils compared to the water can be
varied to modulate the release rate of the terbutaline from the
drug delivery system. The pH can also be varied as appropriate or
to affect the release rate or bioadhesiveness of the
formulation.
[0050] One of the surprising, but important aspects of the present
formulation is that it allows the drug to be administered
effectively even during menses. The particular bioadhesive
qualities prevent the composition from being diluted or washed
away, as would be expected with other bioadhesive preparations.
This characteristic increases the utility of the present
formulation.
[0051] Additionally, in light of the information disclosed in U.S.
Pat. No. 5,543,150, it now appears that this bioadhesive
formulation can provide local vaginal administration of different
drugs to yield significant local drug levels while maintaining
serum levels low enough to avoid most undesired side effects. It
was a surprising result that this formulation serves as an
acceptable carrier for two different active
ingredients-progesterone, and now terbutaline. Now, given its
demonstrated flexibility and range of efficacy, it is reasonable to
expect that the bioadhesive formulation will work with other active
ingredients as well.
EXAMPLES
Example 1
The Pharmacokinetic Parameters of the Terbutaline Composition, A
Single Dose Study
[0052] The objective of this study was to assess the
pharmacokinetic parameters of the terbutaline and polycarbophil
composition following a single dose regimen comparing progressively
increasing concentrations. This open-label study was conducted in
ten healthy female volunteers with a mean age of 25.+-.SD (Standard
Deviation) of 3.93 years. This study consisted of a 30 day
screening period and a 24 hour treatment period with a follow-up
evaluation conducted two days after administration of the final
dose. The drug was administered transvaginally at 9:00 a.m. A wash
out period of at least one week as observed between each of the
four doses of the drug. All subjects were given an
estro-progestative pill, to ensure that all study participants were
at the same point in their menstrual cycle. They began dosing on
day 7 to 10 of their pill intake for the single dose study. Serum
terbutaline concentrations were obtained from blood samples
collected predosing on the mornings of treatment, at frequent
intervals during the initial 24 hours post dose (0.5, 1, 1.5, 2, 4,
6, 8, 12, 24 hours) and at 48 hours post dose. Serum terbutaline
concentrations were determined using gas chromatography-mass
spectrometry. Pharmacokinetic parameters were computed using
concentration-time data for each subject following intake of the
last dose of investigational drug on the morning of study day 6.
The following pharmacokinetic parameters were computed: area under
the drug concentration-time curve from time 0 to time t
(AUC.sub.0-t), where t is the time of the last measurable
concentration; peak drug concentration (C.sub.max); time to peak
drug concentration (t.sub.max); steady state drug concentration
(C.sub.SS); and, elimination half-life (t.sub.1/2).
[0053] All ten subjects completed the study for the 0.1%, 0.2%, and
0.4% (w/w) concentrations. For each dose, the onset of serum
terbutaline concentrations occurred within 1 to 2 hours. (See FIG.
1 and Table 2 showing terbutaline concentrations for each tested
dose). Terbutaline concentrations increased slowly reaching
C.sub.max after 13-14 hours and thereafter remained flat (steady
state) for 24 hours with a mean steady state concentration
(C.sub.SS) of approximately 300 pg/mL with the 0.4% concentration.
Concentrations were still detectable for up to 48 hours
(mean.+-.SEM (Standard Error of the Mean) of 113.11.+-.32.25 pg/mL
for the 0.4% concentration). Terbutaline absorption exhibited
dose-dependent pharmacokinetics as reflected by the increase in
AUC.sub.0-48 values (see Table 2 and FIG. 1) to increases in
terbutaline dosing. Mean t.sub.1/2 estimates varied from 18 to 29
hours according to the dose administered and markedly exceeded
measured t.sub.1/2 after terbutaline administration by intravenous
or subcutaneous routes, as had been found in the prior art.
2TABLE 2 Single Dose Study, Pharmacokinetic Parameters Single Dose
Study Pharmacokinetic Parameters (mean .+-. SEM) Terbutaline Dose n
C.sub.max (pg/mL) T.sub.max (h) C.sub.ss (pg/mL) t.sub.1/2 (h)
AUC.sub.0 to 48 (pg.h/mL) 0.1% 10 117 .+-. 59 13 .+-. 6 56 .+-. 41
18 .+-. 12 2281 .+-. 1836 0.2% 10 297 .+-. 170 13 .+-. 6 191 .+-.
108 29 .+-. 15 8011 .+-. 4699 0.4% 10 479 .+-. 149 14 .+-. 7 294
.+-. 115 24 .+-. 16 11893 .+-. 5277
Example 2
The Pharmacokinetic Parameters of the Terbutaline Composition, A
Multiple Dose Study
[0054] The multiple dose study was an open-label study conducted in
12 healthy female volunteers with a mean age.+-.SD of 25.+-.4.13
years. The dose used in this study was 0.4%. This study consisted
of a 30 day screening period, a 6 day treatment period, and a 2 day
follow-up. The drug was administered transvaginally once daily at
9:00 a.m. All subjects were given an estro-progestative pill, to
ensure that all study participants were at the same place in their
menstrual cycle. They began dosing on day 13 to 16 of their pill
intake for the multiple dose study. Serum terbutaline
concentrations were obtained from blood samples collected predosing
on the mornings of treatment, at frequent intervals during the
initial 24 hours post-dose (0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24
hours), and at 48 hours post-dose. Samples were also obtained just
before each administration and at regular intervals after the last
dose (0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours). Serum terbutaline
concentrations were determined using gas chromatography-mass
spectrometry.
[0055] Pharmacokinetic parameters were computed using
concentration-time data for each subject following intake of the
last dose of investigational drug on the morning of study day 6.
The following pharmacokinetic parameters were computed: area under
the drug concentration-time curve from time 0 to time t
(AUC.sub.0-t), where t is the time of the last measurable
concentration; peak drug concentration (C.sub.max); time to peak
drug concentration (t.sub.max); steady state drug concentration
(C.sub.SS); and, elimination half life (t.sub.1/2). Eleven subjects
completed the study, with one subject withdrawing from the study
due to lipothymia occurring just before first dose administration
and recurring 30 minutes after the first dose. Pharmacokinetic
parameters are presented in FIG. 2 and Table 3. C.sub.max was
reached after approximately 9 hours (477.+-.259 pg/mL) on day 1 and
was multiplied by approximately two-fold on day 6. Moreover, it
remained well below the known threshold susceptible to trigger
systemic adverse events such as tachycardia and tremor, the latter
reported as being approximately 3,000-3,500 pg/mL. Terbutaline
steady state concentration was achieved after the first dose
(mean.+-.SEM: 287.+-.96 pg/mL). The mean C.sub.SS was 10 to 15
times less than therapeutic concentrations of terbutaline for
intravenous preterm labor therapy described in the prior art. See
Lyrenas, S, Grahnen A, Lindberg B. et al., Pharmacokinetics of
Terbutaline During Pregnancy, Eur. J. Clin. Pharmacol., 29:619-23
(1986). Comparison of the AUC.sub.0-24 for days 1 and 6 revealed a
two-fold increase. Mean t.sub.1/2 estimates were 51 hours on day
6.
3TABLE 3 Multiple Dose Study, Pharmacokinetic Parameters Multiple
Dose Study Pharmacokinetic Parameters (mean .+-. SEM) Terbutaline
C.sub.max T.sub.max C.sub.ss AUC.sub.0 to 48 Dose Day n (pg/mL) (h)
(pg/mL) t.sub.1/2 (h) (pg .multidot. h/ml) 0.4% 1 11 477 .+-. 259 9
.+-. 6 287 .+-. 96 -- 6896 .+-. 2304 0.4% 6 11 769 .+-. 465 9 .+-.
5 563 .+-. 339 51 .+-. 91 13512 .+-. 8135
Example 3
A Dose Comparison
[0056] Both the single and multiple dose studies discussed in the
preceding examples also evaluated the 0.8% w/w concentration. The
average age.+-.SD for the single and multiple dose studies at the
0.8 dose were 26.+-.3.42 and 26.+-.4.12, respectively. The
pharmacokinetic parameters from the study follow in Tables 4 and
5.
4TABLE 4 Single Dose Study, Pharmacokinetic Parameters Single Dose
Study Pharmacokinetic Parameters (mean .+-. SEM) Terbutaline Dose n
C.sub.max (pg/mL) T.sub.max (h) C.sub.ss (pg/mL) t.sub.1/2 (h)
AUC.sub.0 to 48 (pg.h/mL) 0.8% 8 787 .+-. 434 10 .+-. 3 579 .+-.
300 20 .+-. 7 23222 .+-. 13530
[0057]
5TABLE 5 Multiple Dose Study, Pharmacokinetic Parameters Multiple
Dose Study Pharmacokinetic Parameters (mean .+-. SEM) Terbutaline
C.sub.max T.sub.max C.sub.ss AUC.sub.0 to 48 Dose Day n (pg/mL) (h)
(pg/mL) t.sub.1/2 (h) (pg .multidot. h/ml) 0.8% 1 10 794 .+-. 394
11 .+-. 5 567 .+-. 322 -- 13618 .+-. 7718 0.8% 6 10 1537 .+-. 906 9
.+-. 2 1135 .+-. 679 19 .+-. 4 27246 .+-. 16299
[0058] As can be seen in FIGS. 3 and 4, the serum terbutaline
levels in both cases did not reach known levels for toxicity (3000
pg/ml), nor did they even therapeutic concentrations for other
conditions such as asthma (1600 pg/ml). A number of patients in the
study (40%), however, experienced side effects such as tachycardia
at this dose. The occurrence of adverse events at this dose was an
unexpected result of the invention, as again the serum levels did
not reach known levels for toxicity. This dose can be a method of
practicing the invention, but is certainly not the most preferred
embodiment.
Example 4
Human Ex Vivo Uterine Perfusion Model
[0059] This model verifies the preferential direct delivery of
terbutaline from the vagina to the uterus. In this study, uteri
obtained from women undergoing hysterectomies for benign diseases
were immediately connected to an organ perfusion system in which
temperature, CO.sub.2 concentration, uterine artery pressure and
flow were maintained constant. A perfusion model was opened without
recirculation. The direct transfer of terbutaline from the vagina
to the uterus was analyzed by applying a mixture of tritiated
[.sup.3H] terbutaline and unlabeled terbutaline to the cuff of
vaginal tissue remaining attached to the cervix after the
hysterectomy. Tritiated terbutaline was only used for
autoradiography analysis of sections of uterine tissue. The
experiments were interrupted at predetermined time intervals after
vaginal applications (3 to 12 hours). At the end of the perfusion
period, .sup.3H and .sup.14C radioactivity was measured in
endometrial and myometrial samples. Tritiated water and .sup.14C
dextran helped to determine that the extend of non-specific vagina
to uterus transport (due to leaks of the system) was less than 10%.
The myometrial extraction of terbutaline and its corresponding
venous outflow during the 12 hour uterine perfusions are shown in
FIG. 3 below. The .sup.3H terbutaline started to be recovered in
the venous effluent uterine during the first 3 hours.
[0060] Terbutaline flow was maximal at the 6th-9th hour and then
decreased for up to 48 hours of perfusion. Terbutaline flow in the
venous effluent uterine is the reflection of terbutaline exiting
from the organ. Accumulation of tritiated terbutaline was maximal
in the myometrium at 12 hours of perfusion. (Mean.+-.SD of
18.40.+-.3.40 ng/100 mg of tissue) and decreased slowly.
Significant accumulation of .sup.3H terbutaline still remained at
48 hours of perfusion, with 20% of the original concentration
present.
[0061] These data demonstrate that a FIRST UTERINE PASS EFFECT.RTM.
also occurs when terbutaline is delivered vaginally. The nature of
the active ingredient and the utilized bioadhesive delivery system
of the present invention seem even to be responsible for a more
delayed and prolonged delivery of vaginal terbutaline gel than the
one described for vaginal progesterone. Indeed, it is unexpected
that the maximal myometrial concentration of terbutaline occurred
later than that for progesterone. Further, it is notable that
terbutaline in the myometrium was shown to last over 48 hours after
a single vaginal application. Vaginal terbutaline gel achieves high
myometrial concentrations of terbutaline relative to its low
systemic concentrations and, consequently, to maximizes utero
relaxant effects and minimizes systemic adverse effects.
[0062] Any and all publications and patent applications mentioned
in this specification are indicative of the level of skill of those
skilled in the art to which this invention pertains. All
publications and patent applications are herein incorporated by
reference to the same extent as if each individual publication or
patent application was specifically and individually indicated to
be incorporated by reference.
[0063] Reasonable variations, such as those which would occur to a
skilled artisan, can be made herein without departing from the
spirit and scope of the invention.
* * * * *